Heart failure is the scourge of the elderly accounting for nearly $35 billion dollars and causing substantial morbidity and mortality; ~50% of all aged patients with CHF have heart failure with a preserved ejection fraction (HFpEF), a multi-factorial condition associated with several abnormalities in diastolic function. Stimulated by previous work from this research program the global objective of the next 5 years is to test novel strategies to prevent and reverse the impaired diastolic function associated with sedentary aging and HFpEF. These include: A) novel exercise training strategies implemented early enough in life while CV plasticity still exists; and B) pharmacologic probes of underlying pathophysiology targeted to improve relaxation in the elderly and HFpEF patients, and restore functional capacity. The aims of the program are: Specific Aim 1: to test the hypothesis that exercise training implemented 4-5 times/week for 2 yrs in sedentary middle aged men and women (45-64yr) will improve cardiac and vascular compliance to a degree equivalent to life-long exercisers (and sedentary young). We will perform invasive and non-invasive assessment of cardiovascular structure and function before and after an exercise program involving high intensity aerobic intervals, lower intensity endurance and strength training or yoga control. Specific Aim 2: to test the hypothesis that the stiff, slowly relaxing heart of patients with HFpEF causes a marked elevation in pulmonary capillary pressure during exercise which leads to premature fatigue prior to achieving maximal HR, thus causing apparent chronotropic incompetence. We further hypothesize that both sedentary aged and HFpEF patients have slowed relaxation due to down regulation of SERCA2a activity, the putative cellular mechanism underlying age related impaired lusitropic function. We plan to perform 2 sets of experiments for this aim: 1) to measure the HR response to two separate interventions: a) maximal activation of central cardiovascular pathways (central command) from static handgrip at 40% maximal voluntary contraction to fatigue; b) incremental doses of isoproterenol in the face of ganglionic blockade to isolate adrenergic responsiveness without reflex compensation; and 2) to perform invasive and non-invasive assessment of cardiac function at rest and during exercise in patients with HFpEF compared to age matched and young controls: a) after infusion of istaroxime an experimental drug with prominent lusitropic properties due to its ability to upregulate SERCA2a activity; and b) after Na+/K+ ATPase inhibition control (digoxin). After these aims are accomplished, we will have established a novel, practical exercise training strategy designed to prevent the cardiovascular stiffening with aging, and ultimately to prevent HFpEF. Such a determination would have enormous public health significance since this condition is quite difficult to treat once established. In addition, we will use novel physiological and pharmacological probes to determine the mechanism of the apparent chronotropic incompetence and impaired exercise capacity in patients with HFpEF which has the potential to open up new therapeutic options for this challenging syndrome.